A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs. Efficacy, time course, and role of KATP channels.

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Abstract
BACKGROUND Adenosine has been proposed to be an important mediator of ischemic preconditioning. Intracoronary administration of adenosine has recently been shown to mimic the effects of preconditioning in isolated rabbit hearts. However, it is not known whether this agent can duplicate the effects of preconditioning in vivo or in other species. Thus, the first objective of the present study was to determine whether adenosine can limit myocardial necrosis to the same extent as preconditioning in anesthetized dogs. A second objective was to determine whether the duration of the adenosine-induced cardioprotection persisted as long as that of ischemic preconditioning. Finally, a third aim was to determine whether adenosine mediates its cardioprotection via the KATP channel, which has been shown to be an important mediator of preconditioning in several animal species, including dogs. METHODS AND RESULTS Barbital-anesthetized open-chest dogs were subjected to 60 minutes of left anterior descending coronary artery (LAD) occlusion followed by 4 hours of reperfusion. Preconditioning was elicited by 10 minutes of LAD occlusion followed by 10 or 60 minutes of reperfusion before the 60-minute occlusion period. Adenosine (400 micrograms/min) or an equivalent volume of saline was infused into the LAD for 10 minutes, followed by a 10- or 60-minute drug-free period before the 60-minute ischemic insult. Glibenclamide (0.3 mg/kg i.v.), a selective KATP channel blocker, was given 15 minutes before adenosine administration, and another selective KATP channel blocker, 5-hydroxydecanoate (5-HD, 3 mg/min IC) was infused concomitantly with adenosine into the LAD for 10 minutes. Transmural myocardial blood flow was measured at 5 minutes of occlusion, and infarct size was determined by triphenyltetrazolium staining and expressed as a percent of the area at risk (AAR). There were no significant differences in hemodynamics, collateral blood flow, or AAR between groups. Preconditioning with either 10 or 60 minutes of reperfusion produced a marked reduction (P < .05) in infarct size (6.7 +/- 2.5% and 8.7 +/- 2.6%, respectively, versus 26.9 +/- 4.3% in controls). Administration of adenosine with a 10-minute drug-free period before 60 minutes of occlusion resulted in a marked decrease in infarct size similar to that seen with preconditioning (9.6 +/- 1.7% versus 26.9 +/- 4.3% in controls); however, the protection disappeared when a 60-minute drug-free period was allowed after adenosine administration (23.0 +/- 2.4% versus 26.9 +/- 4.3% in controls). In addition, treatment with either glibenclamide or 5-HD completely abolished the protective effects of adenosine (26.4 +/- 6.8 and 25.0 +/- 4.4%, respectively, versus 26.9 +/- 4.3% in controls). CONCLUSIONS These results clearly reveal that (1) a 10-minute intracoronary infusion of adenosine exhibits the same efficacy as ischemic preconditioning in reducing myocardial necrosis in dogs; (2) similar to preconditioning, adenosine mediates its cardioprotection via a cardiac KATP channel-linked mechanism; and (3) adenosine-induced cardioprotection is transient (disappearing within 60 minutes), whereas ischemic preconditioning persists for at least 60 minutes. These data support the hypothesis that endogenous adenosine released during ischemia is an important mediator of ischemic preconditioning; however, important differences exist between the time course of effects of exogenously administered adenosine and preconditioning, which suggests that other factors may also be involved.